Ribosomal Protein S6 Kinase 1 Signaling Regulates Mammalian Life Span

Abstract

Caloric restriction (CR) protects against aging and disease but the mechanisms by which this affects mammalian lifespan are unclear. We show in mice that deletion of the nutrient-responsive mTOR (mammalian target of rapamycin) signaling pathway component ribosomal S6 protein kinase 1 (S6K1) led to increased lifespan and resistance to age-related pathologies such as bone, immune and motor dysfunction and loss of insulin sensitivity. Deletion of S6K1 induced gene expression patterns similar to those seen in CR or with pharmacological activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK), a conserved regulator of the metabolic response to CR. Our results demonstrate that S6K1 influences healthy mammalian lifespan, and suggest therapeutic manipulation of S6K1 and AMPK might mimic CR and provide broad protection against diseases of aging. Genetic studies in S. cerevisiae, C. elegans and D. melanogaster implicate several mechanisms in the regulation of lifespan. These include the insulin and insulin-like growth factor 1 (IGF-1) signaling (IIS) and mammalian target of rapamycin (mTOR) pathways which both activate the downstream effector ribosomal protein S6 kinase 1 (S6K1) (1, 2). Although the role of these pathways in mammalian aging is less clear, there is mounting evidence that IIS regulates lifespan in mice (1). Global deletion of one allele of the IGF1 receptor (Igf1r), adipose-specific deletion of the insulin receptor (Insr), global deletion of insulin receptor substrate protein 1 (Irs1) or neuron-specific deletion of Irs2 all increase mouse lifespan (1). Lifespan-extending mutations in the somatotropic axis also appear to work through attenuated IIS (3). Igf1r has also been implicated as a modulator of human longevity (4). However, the action of downstream effectors of IIS or mTOR signaling in mammalian longevity is not fully understood.S6K1 transduces anabolic signals that indicate nutritional status to regulate cell size and growth and metabolism through various mechanisms (5). These include effects on the translational machinery and on cellular energy levels through the activity of adenosine monophosphate (AMP)-activated protein kinase (AMPK) (6, 7). Furthermore, S6K1 serine phosphorylates IRS1 and IRS2 thereby decreasing insulin signaling (5). Given the key role of S6K1 in IIS and mTOR signaling, and the regulation of aging in lower organisms by mTOR, S6K, and their downstream effectors (2) we used log rank testing to evaluate differences in lifespan of wild-type (WT) and S6K1 -/-littermate mice on a C57BL/6 background (8). Data for both sexes combined showed median lifespan in S6K1 -/-mice increased by 80 days (from 862 to 942 days) or 9% relative to that of WT mice (X 2 = 10.52, p < 0.001) ( Fig. 1A and Table 1). Maximum lifespan (mean lifespan of the oldest 10% within a cohort) was also increased (1077±16 and 1175±24 days, p < 0.01 for WT and S6K1 -/-mice, respectively). Analysis of each sex separately showed that median lifespan in female S6K1 -/-mice was increased, by 153 d...

Age‐associated microRNA expression in human peripheral blood is associated with all‐cause mortality and age‐related traits

“…In C. elegans studies, reducing the levels of key proteins involved in translation, such as ribosomal proteins, ribosomal‐protein S6 kinase, and translation initiation factors, increased the lifespan of C. elegans (Hansen et al ., 2007; Pan et al ., 2007). Ribosomal‐protein S6 kinase also regulates lifespan in mammalian models (Selman et al ., 2009). miRNAs in Drosophila have been shown to block the eIF4F translation initiation complex assembly, thereby inhibiting overall translation of protein‐coding genes (Fukaya et al ., 2014).…”

Sex‐ and tissue‐specific changes in mTOR signaling with age in C57 BL /6J mice

“…While the basis for this difference is unknown, higher mTORC1 signaling in female C57BL/6J.Nia mice correlates with both their slightly shorter lifespan relative to males, and to the greater increase in lifespan female mice show following treatment with rapamycin (Turturro et al ., 1999; Fok et al ., 2014). The differences observed here may also contribute to the sexually dimorphic impact of S6K1 deletion on lifespan (Selman et al ., 2009). …”

“…Rapamycin is an acute inhibitor of mTORC1 (mechanistic Target Of Rapamycin Complex 1), which regulates numerous cellular processes including ribosomal biogenesis, protein translation, and autophagy through the phosphorylation of substrates that include S6K1, 4E‐BP1, and Ulk1 (Laplante & Sabatini, 2012). Mice lacking S6K1 or with decreased mTORC1 activity have extended lifespan, demonstrating that decreased mTORC1 signaling is sufficient to promote longevity, at least in females (Selman et al ., 2009; Lamming et al ., 2012). A similar inverse correlation between hepatic mTORC1 signaling and lifespan is also observed in wild‐type mice (Solon‐Biet et al ., 2014).…”

Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system

“…Rapamycin is an acute inhibitor of the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1), a protein kinase which regulates numerous cellular processes including ribosomal biogenesis, protein translation, and autophagy through the phosphorylation of substrates that include S6K1, 4E‐BP1, and Ulk1. Mice lacking S6K1 or with decreased mTORC1 activity have extended longevity, demonstrating that decreased mTORC1 signaling is sufficient to promote longevity, especially in females (Selman et al ., 2009; Lamming et al ., 2012; Wu et al ., 2013). …”